Study to Evaluate the Safety and Efficacy of Tislelizumab in Combination With Zanidatamab as a 2nd Line in HER2-Positive Advanced Gastric Cancer in K-Umbrella Trial

Inclusion Criteria: 1. Able to provide written informed consent and can understand and agree to comply with the requirements of the study and the schedule of assessments 2. Age ≥19 years on the day of signing the informed consent form (or the legal age of consent in the jurisdiction in which the study is taking place) 3. Has a histologically or cytologically confirmed diagnosis of advanced gastric /GEJ adenocarcinoma (systemic metastasis or locally advanced unresectable gastric/GEJ adenocarcinoma) 4. Progressed from prior 1st line systemic chemotherapy (no more than one previous line of treatment is allowed; trastuzumab or other anti-HER2 therapy is acceptable as prior treatment, except for zanidatamab) 5. Has a documented HER2-positive tumor in primary or metastatic tumor tissue 1. HER2-positive tumor defined as either IHC 3+; OR 2. IHC 2+ in combination with SISH + (or FISH), as assessed by local laboratory on primary or metastatic tumor (SISH positivity is defined as a ratio of ≥2.0 for the number of HER2 gene copies to the number of signals for CEP17) 6. Has measurable disease as determined by RECIST 1.1 (A lesion which received prior radiotherapy cannot be a measurable lesion.) 7. Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1 8. LVEF ≥50% as determined by either echocardiogram or multiple gated acquisition scan (MUGA) 9. Adequate organ function as indicated by the following laboratory values during screening a. Patients must not have required a blood transfusion or growth factor support ≤14 days before sample collection at screening for the following: i. Absolute neutrophil count (ANC) ≥1.5 x 109/L ii. Platelets ≥75 x 109/L iii. Hemoglobin ≥90 g/L b. Serum creatinine ≤1.5 x ULN (upper limit of normal) or estimated Glomerular Filtration Rate ≥60 mL/min/1.73 m2 (Appendix 8) c. Serum total bilirubin ≤1.5 x ULN (total bilirubin must be \<3 x ULN for patients with Gilberts syndrome) d. AST and ALT ≤3 x ULN 10. Females of childbearing potential must be willing to use a highly effective method of birth control for the duration of the study, and for 7 months after the last dose of study drugs, and have a negative urine or serum pregnancy test ≤7 days of first dose of study drug (Appendix 9) 11. Non-sterile males must be willing to use a highly effective method of birth control for the duration of the study and for 7 months after the last dose of study drugs (Appendix 9) 12. Male subjects must agree not to donate sperm and female subjects must agree not to donate oocytes starting at screening and throughout the study period, and for 7 months after treatment discontinuation Exclusion Criteria: 1. Have previously received zanidatamab (trastuzumab or other anti-HER2 therapy is acceptable as a prior treatment). 2. Have previously received Tislelizumab, anti-programmed cell death-1 (PD-1) antibody, anti-PD-L1 antibody, anti-programmed cell death-ligand 2 (PD-L2) antibody, anti-CD137 antibody, anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) antibody, or other therapeutic antibodies or pharmacotherapies for the regulation of T-cells. 3. Active leptomeningeal disease or uncontrolled brain metastasis. Patients with equivocal findings or with confirmed brain metastases are eligible for enrollment provided that they are asymptomatic and radiologically stable without the need for corticosteroid treatment for ≥ 4 weeks before first dose of study drug. Note: Eligibility with regards to the anatomical location of brain metastasis, and requiring patients with new asymptomatic metastasis to receive radiotherapy/surgery before enrolling in this study, will be determined per investigator's medical judgement and consultation. 4. Active autoimmune diseases or history of autoimmune diseases that may relapse. Note: Patients with the following diseases are not excluded and may proceed to further screening: 1. Controlled Type I diabetes 2. Hypothyroidism (provided it is managed with hormone replacement therapy only) 3. Controlled celiac disease 4. Skin diseases not requiring systemic treatment (e.g., vitiligo, psoriasis, alopecia) 5. Any other disease that is not expected to recur in the absence of external triggering factors 5. Any active malignancy ≤2 years before first dose of study drug except for the specific cancer under investigation in this study and any locally recurring cancer that has been treated curatively (e.g., resected basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of the cervix or breast). 6. Any condition that required systemic treatment with either corticosteroids (\>10 mg daily of prednisone or equivalent) or other immunosuppressive medication ≤14 days before first dose of study drug. Note: Patients who are currently or have previously been on any of the following steroid regimens are not excluded: 1. Adrenal replacement steroid (dose ≤ 10 mg daily of prednisone or equivalent) 2. Topical, ocular, intra-articular, intranasal, or inhaled corticosteroid with minimal systemic absorption 3. Short course (≤7 days) of corticosteroid prescribed prophylactically (e.g., for contrast dye allergy) or for the treatment of a non-autoimmune condition (e.g., delayed-type hypersensitivity reaction caused by contact allergen) 7. With uncontrolled diabetes or \>Grade 1 laboratory test abnormalities in potassium, sodium, or corrected calcium despite standard medical management or ≥Grade 3 hypoalbuminemia ≤14 days before first dose of study drug. 8. With history of interstitial lung disease, non-infectious pneumonitis or uncontrolled diseases including pulmonary fibrosis, acute lung diseases, etc.; an assessment of pulmonary function will be conducted at screening (see Section 7.1.4) 9. With severe chronic or active infections requiring systemic antibacterial, antifungal or antiviral therapy, including tuberculosis infection, etc. * Severe infections within 4 weeks before or first dose of study drug, including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia * Received therapeutic oral or intravenous antibiotics within 2 weeks before first cycle of study drug 10. A known history of HIV infection. 11. Patients with untreated chronic hepatitis B or chronic hepatitis B virus (HBV) carriers whose HBV DNA is \>500 IU/mL or patients with active hepatitis C virus (HCV) should be excluded. Note: Inactive hepatitis B surface antigen (HBsAg) carriers, treated and stable hepatitis B (HBV DNA \<500 IU/mL), and cured hepatitis C patients can be enrolled. 12. Any major surgical procedure requiring general anesthesia ≤28 days before first dose of study drug. 13. Prior allogeneic stem cell transplantation or organ transplantation. 14. Any of the following cardiovascular risk factors: 1. Cardiac chest pain, defined as moderate pain that limits instrumental activities of daily living, ≤28 days before first dose of study drug 2. Pulmonary embolism ≤28 days before first dose of study drug 3. Any history of acute myocardial infarction ≤6 months before first dose of study drug 4. Any history of heart failure meeting New York Heart Association (NYHA) Classification III or IV ≤6 months before first dose of study drug (Appendix 6) 5. Any event of ventricular arrhythmia ≥Grade 2 in severity ≤6 months before first dose of study drug 6. Any history of cerebrovascular accident ≤6 months before first dose of study drug 7. Uncontrolled hypertension: systolic pressure ≥160 mmHg or diastolic pressure ≥100 mmHg despite anti-hypertension medications ≤28 days before first dose of drug 8. Any episode of syncope or seizure ≤28 days before first dose of study drug 15. A history of severe hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins. 16. Has received any chemotherapy, immunotherapy (e.g., interleukin, interferon, thymosin) or any investigational therapies within 28 days or 5 half-lives (whichever is shorter) of the first study drug administration. 17. Has received any herbal medicine used to control cancer within 14 days of the first study drug administration. 18. Patients with toxicities (as a result of prior anticancer therapy) which have not recovered to baseline or stabilized, except for AEs not considered a likely safety risk (e.g., alopecia, neuropathy and specific laboratory abnormalities). 19. Was administered a live vaccine ≤4 weeks before first dose of study drug. Note: Seasonal vaccines for influenza are generally inactivated vaccines and are allowed. COVID-19 vaccines are allowed if not live vaccines. Intranasal vaccines are live vaccines, and are not allowed. 20. Underlying medical conditions (including laboratory abnormalities) or alcohol or drug abuse or dependence that, will be unfavorable for the administration of study drug or affect the explanation of drug toxicity or AEs or result in insufficient or might impair compliance with study conduct. 21. Concurrent participation in another therapeutic clinical study. 22. Has QT corrected (QTc) interval (corrected by Fridericia's method) \>470 msec (if applicable). Note: If any patient has QTc interval \>450 msec on initial ECG, follow up ECG will be performed \[in triplicate\] to exclude result 23. Received radiation therapy within 14 days prior to randomization. 24. Total lifetime anthracycline load exceeding 360 mg/m2 doxorubicin or equivalent. 25. Acute or chronic uncontrolled renal disease, pancreatitis, or liver disease (with exception of subjects with Gilbert's Syndrome, asymptomatic gall stones, liver metastases, or stable chronic liver disease per investigator assessment). 26. Females who are breastfeeding or pregnant, and females and males planning a pregnancy. 27. With the following disease-related risk factors: 1. Clinically significant bleeding (≥Grade 3) from the gastrointestinal (GI) tract within 4 weeks prior to randomization 2. Clinically significant bowel obstruction (≥Grade 3) 28. Accumulation of pleural, ascitic, or pericardial fluid requiring drainage or diuretic drugs within 2 weeks prior to randomization. Receipt of diuretic drugs for other reasons is acceptable